A Tumour-Specific Molecular Network Promotes Tumour Growth in Drosophila by Enforcing a JNK-YKI Feedforward Loop

Abstract

Cancer cells expand rapidly in response to altered intercellular and signalling interactions to achieve hallmarks of cancer. Impaired cell polarity combined with activated oncogenes is known to promote several hallmarks of cancer e.g., activating invasion by increased activity of Jun N-terminal kinase (JNK), and sustained proliferative signalling by increased activity of Hippo effector Yorkie (Yki). Thus, JNK, Yki, and their downstream transcription factors have emerged as synergistic drivers of tumour growth through pro-tumour signalling and intercellular interactions like cell-competition. However, little is known about the signals that converge onto JNK and Yki in tumour cells that enable the tumour cells to achieve hallmarks of cancer. Here, using mosaic models of cooperative oncogenesis (RasV12, scrib-) in Drosophila, we show that RasV12, scrib- tumour cells grow by activation of a previously unidentified network comprising Wingless (Wg), Dronc, JNK and Yki. We show that RasV12, scrib- cells show increased Wg, Dronc, JNK, and Yki signalling, and all of these signals are required for the growth of RasV12, scrib- tumours. We report that Wg and Dronc converge onto a JNK-Yki self-reinforcing positive feedback signal-amplification loop that promotes tumour growth. We found that Wg-Dronc-Yki-JNK molecular network is specifically activated in polarity-impaired tumour cells and not in normal cells where apical basal polarity is intact. Our findings suggest that identification of molecular networks may provide significant insights about the key biologically meaningful changes in signalling pathways, and paradoxical signals that promote Tumourigenesis.